EP4008317A1 - Solid pharmaceutical formulations of amorphous dapagliflozin - Google Patents
Solid pharmaceutical formulations of amorphous dapagliflozin Download PDFInfo
- Publication number
- EP4008317A1 EP4008317A1 EP21211906.9A EP21211906A EP4008317A1 EP 4008317 A1 EP4008317 A1 EP 4008317A1 EP 21211906 A EP21211906 A EP 21211906A EP 4008317 A1 EP4008317 A1 EP 4008317A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- solid pharmaceutical
- pharmaceutical formulation
- formulation according
- tablet
- amorphous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 title claims abstract description 44
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
- 239000007787 solid Substances 0.000 title claims abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 16
- 238000009472 formulation Methods 0.000 claims abstract description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 239000003826 tablet Substances 0.000 claims description 23
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 14
- 229960003105 metformin Drugs 0.000 claims description 13
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 12
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 12
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 10
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 9
- 229960004977 anhydrous lactose Drugs 0.000 claims description 9
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 239000000945 filler Substances 0.000 claims description 7
- 239000007941 film coated tablet Substances 0.000 claims description 7
- 239000012458 free base Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 6
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 6
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 6
- 229960000913 crospovidone Drugs 0.000 claims description 6
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 229940032147 starch Drugs 0.000 claims description 6
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 5
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 5
- 239000000454 talc Substances 0.000 claims description 5
- 229910052623 talc Inorganic materials 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 239000000395 magnesium oxide Substances 0.000 claims description 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 4
- 229960000869 magnesium oxide Drugs 0.000 claims description 4
- 235000012245 magnesium oxide Nutrition 0.000 claims description 4
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 4
- 239000008188 pellet Substances 0.000 claims description 4
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 claims description 4
- 229960004937 saxagliptin Drugs 0.000 claims description 4
- 108010033693 saxagliptin Proteins 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- 238000002648 combination therapy Methods 0.000 claims description 3
- -1 gums Substances 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims description 3
- 229960004034 sitagliptin Drugs 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 claims description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 2
- 239000006189 buccal tablet Substances 0.000 claims description 2
- 229940046011 buccal tablet Drugs 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 229960003563 calcium carbonate Drugs 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 claims description 2
- 229940078495 calcium phosphate dibasic Drugs 0.000 claims description 2
- 239000001175 calcium sulphate Substances 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- VLCINIKIVYNLPT-UHFFFAOYSA-J dicalcium;hydrogen phosphate Chemical compound [Ca+2].[Ca+2].OP(O)([O-])=O.[O-]P([O-])([O-])=O VLCINIKIVYNLPT-UHFFFAOYSA-J 0.000 claims description 2
- 239000007938 effervescent tablet Substances 0.000 claims description 2
- 235000010944 ethyl methyl cellulose Nutrition 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 229960001708 magnesium carbonate Drugs 0.000 claims description 2
- 239000000391 magnesium silicate Substances 0.000 claims description 2
- 235000019792 magnesium silicate Nutrition 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
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- 229940035034 maltodextrin Drugs 0.000 claims description 2
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- MLCUESNGPCTHAL-UHFFFAOYSA-H tricalcium diphosphate trihydrate Chemical compound O.O.O.[Ca++].[Ca++].[Ca++].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O MLCUESNGPCTHAL-UHFFFAOYSA-H 0.000 claims description 2
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 claims 1
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- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Chemical class 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Chemical class 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000037221 weight management Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
Definitions
- the present invention relates to a solid pharmaceutical formulation comprising amorphous dapagliflozin and at least one pharmaceutically acceptable excipient. Further, the formulations comprising amorphous dapagliflozin are prepared a method which is simple, rapid, cost effective, time-saving and industrially convenient process.
- Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors.
- Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged.
- Type 1 diabetes the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy.
- People with Type 1 diabetes must use insulin injections to control their blood glucose.
- Type 2 diabetes the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweight and type 2 diabetes is the most common type, affecting more than 171 million people worldwide.Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
- Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2).
- SGLT2 is a carrier responsible for the reabsorption of most of the glucose from the lumen of the renal tubule.
- SGLT2 is expressed in proximal renal tubules.
- dapagliflozin reduces the reabsorption of the filtered glucose and lowers the renal threshold for glucose. This improves urinary glucose excretion and blood glucose control.
- Dapagliflozin also known as (1S)-1,5-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol or (2S,3R,4R,5S,6R)-2-(3-(4-etoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol is represented by the structure of Formula I.
- Dapagliflozin was first disclosed in patent US 6515117 (2003, Bristol-Myers Squibb ).
- US2008234366 A1 , US2011064801 A1 and US2012263786 A1 disclose pharmaceutical compositions comprising dapagliflozin or dapagliflozin propylene glycol hydrate and specific excipients in given amounts.
- WO2008116178 refers to pharmaceutical formulations which include crystalline dapagliflozin propylene glycol hydrate.
- US2011064801 A1 further discloses pharmaceutical compositions in the form of a stock granulation comprising dapagliflozin propylene glycol hydrate and excipients in given amounts.
- the invention provides an amorphous form of dapagliflozin. Although amorphous forms are sometimes better soluble than crystalline forms, they are often not the preferred form because of water activity and/or stability reasons. However, the present invention eliminates all aforesaid problems and bring additional advantages to the relevant prior art.
- the main object of the present invention is to a solid pharmaceutical formulation comprising amorphous dapagliflozin which has the desired stability, dissolution profile, hardness and compressibility, in another words the disadvantages seen in the active substance in the art, is able to overcome.
- Another object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art and problem of content uniformity which overcomes the above described problems in prior art.
- the invention provides a solid pharmaceutical formulation comprising amorphous dapagliflozin.
- the solid pharmaceutical formulation does not comprise described problems in prior art about active agent.
- the formulation provides long shelf life and high stability during shelf life.
- the solid pharmaceutical formulation comprising amorphous dapagliflozin provides the desired bioavailability.
- a solid pharmaceutical formulation comprising amorphous dapagliflozin and at least one pharmaceutically acceptable excipient.
- 'particle size means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis).
- d (0.1) means, the size at which 10% by volume of the particles are finer and d (0.5) means the size at which 50% by volume of the particles are finer and d (0.9) means the size at which %90 by volume of the particles are finer.
- dapagliflozin having the following particle sizes is very important for formulation. Especially, it positively affects the dissolution properties and powder homogenization.
- the obtained tablets have the desired dissolution profile.
- the powder is more homogeneous.
- the content uniformity of the tablets obtained from the more homogeneous powder is more ideal. Therefore, it provides better bioavailability.
- amorphous dapagliflozine has a d (0.9) particle size between 20 ⁇ m to 140 ⁇ m.
- amorphous dapagliflozine has a d (0.9) particle size between 22 ⁇ m to 130 ⁇ m, between 25 ⁇ m to 120 ⁇ m, between 30 ⁇ m to 110 ⁇ m, between 35 ⁇ m to 100 ⁇ m, between 40 ⁇ m to 98 ⁇ m, between 45 ⁇ m to 95 ⁇ m, between 47 ⁇ m to 90 ⁇ m, between 50 ⁇ m to 85 ⁇ m.
- amorphous dapagliflozine has a d (0.1) particle size between 3 ⁇ m to 60 ⁇ m.
- amorphous dapagliflozine has a d (0.1) particle size between 5 ⁇ m to 55 ⁇ m, between 6 ⁇ m to 50 ⁇ m, between 7 ⁇ m to 45 ⁇ m, between 8 ⁇ m to 40 ⁇ m, between 9 ⁇ m to 30 ⁇ m.
- amorphous dapagliflozine has a d (0.5) particle size between 8 ⁇ m to 90 ⁇ m.
- amorphous dapagliflozine has a d (0.5) particle size between 9 ⁇ m to 85 ⁇ m, between 10 ⁇ m to 80 ⁇ m, between 11 ⁇ m to 75 ⁇ m, between 11 ⁇ m to 70 ⁇ m, between 15 ⁇ m to 60 ⁇ m, between 18 ⁇ m to 55 ⁇ m, between 20 ⁇ m to 50 ⁇ m, between 25 ⁇ m to 45 ⁇ m.
- the amount of amorphous dapagliflozin is 0.05% to 8.0% by weight, preferably 0.05.% to 5.0% by weight in the total composition.
- Dapagliflozin is used small proportion that can lead to considerable problems during the manufacture of the composition with regard to the uniformity of the content of active agent in the individual composition units. Because of problems uniformity of the content, the active substance may interact with several excipients. It reflects that content uniformity play important role in the dissolution of the drug. Using the right excipients is ensured uniformity of the content.
- At least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
- Suitable fillers are selected from the group comprising microcrystalline cellulose, anhydrous lactose, lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, silicon dioxide, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.
- the filler is microcrystalline cellulose or anhydrous lactose.
- the amount of fillers is 5.0% to 92% by weight.
- the amount of fillers is 5.0% to 40.0% or 58.0% to 92.0% by weight in the total composition.
- Suitable binders are selected from the group comprising polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, carboxymethylcellulose sodium, lactose anhydrous, pregelatinized starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulphate, hydroxypropylcellulose, methyl cellulose, ethyl cellulose or mixtures thereof.
- the binder is polyvinylpyrrolidone or hydroxypropylmethylcellulose or carboxymethylcellulose sodium.
- the amount of binders is 0.5% to 15% by weight in the total composition. This amount of binders provides the desired dissolution profile.
- Suitable disintegrants are selected from the group comprising croscarmellose sodium, crospovidone, sodium starch glycollate, sodium alginate, gums, starch and magnesium aluminum silicate or a mixture thereof.
- the disintegrant is croscarmellose sodium or crospovidone.
- the amount of disintegrants is 0.05% to 10.0% by weight, preferably 1.0% to 4.0% by weight in the total composition. This amount of disintegrants provides the desired dissolution profile.
- Suitable glidant are selected from group comprising colloidal silicon dioxide, magnesium oxide, starch, magnesium silicate, colloidal silica or mixtures thereof.
- the glidant is colloidal silicon dioxide.
- the amount of glidants is 0.05% to 3.0% by weight in the total composition.
- Suitable lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, silica colloidal anhydrous, talc, polyethylene glycol, stearic acid, aluminum silicate or mixtures thereof.
- the lubricant is magnesium stearate or sodium stearyl fumarate.
- the amount of lubricants is 0.01% to 5.0% by weight in the total composition.
- modified release formulations in the solid pharmaceutical formulation, can be preferred.
- Modified release formulations are selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof.
- formulation is prepared using matrix agents.
- Suitable matrix agents are selected from the group comprising hydroxypropylmethyl cellulose, ethyl cellulose, polymethylmethacrylate derivatives's, poloxamer, polyvinyl alcohol, xanthan gum, sodium alginate, polymethacrylates, polyacrylamide, semi-synthetic polymers such as methyl cellulose, hydroxypropyl cellulose, polyvinyl acetate, cellulose acetate phthalate, ethylene vinyl acetate, methyl aminoethyl methacrylate, neutral methacrylic acid esters, polylactide, polylactide co-glycolide, low molecular weight polyethylene/polyisobutylene, polyanhydrides and poly (ortho-esters), diethyl aminoethyl methacrylate or mixtures thereof.
- the amount of matrix agents is 10.0% to 30.0% by weight in the total composition.
- the solid pharmaceutical formulation is in the form of film-coated tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, pellet, buccal tablet, sublingual tablet, effervescent tablet, capsule.
- the solid pharmaceutical formulation is in the form of film-coated tablet which comprises at least one film coating agent.
- Suitable film coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, talc, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, glycerin, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat ® IR), ethylcellulose dispersions (Surelease ® ), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), iron oxide yellow, iron oxide, all kinds of Opadry ® , pigments, dyes, titanium dioxide, coloring agent or mixtures thereof.
- the film coating agents are selected from the group comprising polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, iron oxide, iron oxide yellow.
- the amount of film coating agents is 1.0% to 10.0% by weight, preferably 1.5 to 6.0% by weight in the total composition.
- the solid pharmaceutical formulation is in the form of bilayer tablet or multilayer tablet.
- amorphous dapagliflozin is present in a combination therapy.
- combinations can be with at least one dipeptidyl peptidase-4 (DPP-4) inhibitor agent.
- DPP-4 dipeptidyl peptidase-4
- amorphous dapagliflozin and metformin hydrochloride amorphous dapagliflozin and saxagliptin in the form the free base or in the form of pharmaceutically acceptable salts
- amorphous dapagliflozin and saxagliptin in the form the free base or in the form of pharmaceutically acceptable salts and metformin HCI amorphous dapagliflozin and sitagliptin in the form the free base or in the form of pharmaceutically acceptable salts.
- amorphous dapagliflozin is present in a combination therapy which are with metformin HCl or saxagliptin in the form the free base or in the form of pharmaceutically acceptable salts or sitagliptin in the form the free base or in the form of pharmaceutically acceptable salts or mixtures thereof.
- the solid pharmaceutical formulation of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet granulation or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
- Example 1 The film coated tablet
- Active ingredient and excipient Ingredients in one tablet (%) (by weight) Amorphous dapagliflozin 0.05 - 8.0 Microcrystalline cellulose 50.0 - 80.0 Anhydrous lactose 8.0 - 25.0 Crospovidone 1.0 - 10.0 Colloidal silicone dioxide 0.5 - 5.0 Magnesium stearate 0.5 - 5.0 Film coating agents 1.0 - 8.0 Total 100
- Example 2 The film coated tablet
- Active ingredient and excipient Ingredients in one tablet (%) (by weight) Amorphous dapagliflozin 3.8 Microcrystalline cellulose 66.8 Anhydrous lactose 19.2 Crospovidone 3.8 Colloidal silicone dioxide 1.5 Magnesium stearate 1.0 Film coating agents 3.8 Total 100
- Example 3 The film coated tablet comprising amorphous dapagliflozin and metformin HCl
- Active ingredient and excipient Ingredients in one tablet (%) (by weight) Amorphous dapagliflozin 0.05 - 5.0 Metformin HCl 55.0 - 80.0 Polyvinylpyrrolidone 2.0 - 15.0 Microcrystalline cellulose 5.0 - 30.0 Croscarmellose sodium 1.0 - 10.0 Magnesium stearate 0.1 -5.0 Film coating agents 2.0 - 10.0 Total 100
- Example 4 The film coated tablet comprising amorphous dapagliflozin and metformin HCl
- Active ingredient and excipient Ingredients in one tablet (%) (by weight) Amorphous dapagliflozin 0.3 Metformin HCI 68.5 Polyvinylpyrrolidone 5.5 Microcrystalline cellulose 16.8 Croscarmellose sodium 2.4 Magnesium stearate 1.0 Film coating agents 5.5 Total 100
- Example 5 The bilayer tablet having extended release form comprising amorphous dapagliflozin and metformin HCl
- the immediate release layer (first layer) Amorphous dapagliflozin 0.1 -8.0 Microcrystalline cellulose 5.0 - 30.0 Anhydrous lactose 1.0 - 10.0 Croscarmellose sodium 0.05 - 3.0 Colloidal silicon dioxide 0.05 - 3.0 Sodium stearyl fumarate 0.05 - 3.0
- the extended release layer (second layer) Metformin HCI 40.0 - 80.0 At least one matrix agent (for example; hydroxypropyl methylcellulose (HPMC K100 MCR/K100/CN10T)) 10.0 - 30.0 Hydroxypropylmethyl cellulose as binder 0.1 - 6.0 Carboxymethylcellulose sodium 0.5 - 6.0 Magnesium stearate 0.01 - 3.0 Film-coating Film coating agents 1.0 - 8.0 Total of the weight of the bilayer tablet 100
- Example 6 The bilayer tablet having extended release form comprising amorphous dapagliflozin and metformin HCl
- Active ingredient and excipient Ingredients in one layer (%) (by weight)
- the immediate release layer (first layer) Amorphous dapagliflozin 0.6 Microcrystalline cellulose 11.7 Anhydrous lactose 2.9 Croscarmellose sodium 0.9 Colloidal silicon dioxide 0.3 Sodium stearyl fumarate 0.4
- the extended release layer (second layer) Metformin HCI 59.9 At least one matrix agent 16.4 Hydroxypropylmethylcellulose as binder 1.2 Carboxymethylcellulose Sodium 3.0 Magnesium stearate 0.4 Film-coating Film coating agents 2.4 Total of the weight of the bilayer tablet 100
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Abstract
Description
- The present invention relates to a solid pharmaceutical formulation comprising amorphous dapagliflozin and at least one pharmaceutically acceptable excipient. Further, the formulations comprising amorphous dapagliflozin are prepared a method which is simple, rapid, cost effective, time-saving and industrially convenient process.
- Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors. There are two main types of diabetes; Type 1 and Type 2:
Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose. - In Type 2 diabetes, the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweight and type 2 diabetes is the most common type, affecting more than 171 million people worldwide.Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
- Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2). SGLT2 is a carrier responsible for the reabsorption of most of the glucose from the lumen of the renal tubule. SGLT2 is expressed in proximal renal tubules. By inhibiting SGLT2, dapagliflozin reduces the reabsorption of the filtered glucose and lowers the renal threshold for glucose. This improves urinary glucose excretion and blood glucose control. Dapagliflozin, also known as (1S)-1,5-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol or (2S,3R,4R,5S,6R)-2-(3-(4-etoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol is represented by the structure of Formula I.
- Dapagliflozin was first disclosed in patent
US 6515117 (2003, Bristol-Myers Squibb ). -
US2008234366 A1 ,US2011064801 A1 andUS2012263786 A1 disclose pharmaceutical compositions comprising dapagliflozin or dapagliflozin propylene glycol hydrate and specific excipients in given amounts. -
WO2008116178 refers to pharmaceutical formulations which include crystalline dapagliflozin propylene glycol hydrate. -
US2011064801 A1 further discloses pharmaceutical compositions in the form of a stock granulation comprising dapagliflozin propylene glycol hydrate and excipients in given amounts. - Although several solid forms comprising dapagliflozin are known in the art, finding a good or even the optimal form with regard to bioavailability and safety remains a considerable challenge, in particular when the compound forms many polymorphic forms. Not all solid forms comprising dapagliflozin are equally suitable with regard to stability, flow properties, compressibility, dissolution rate.
- In view of the above art, there is still a need for an effective solid pharmaceutical formulation comprising of a form of dapagliflozin. The invention provides an amorphous form of dapagliflozin. Although amorphous forms are sometimes better soluble than crystalline forms, they are often not the preferred form because of water activity and/or stability reasons. However, the present invention eliminates all aforesaid problems and bring additional advantages to the relevant prior art.
- The main object of the present invention is to a solid pharmaceutical formulation comprising amorphous dapagliflozin which has the desired stability, dissolution profile, hardness and compressibility, in another words the disadvantages seen in the active substance in the art, is able to overcome.
- Another object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art and problem of content uniformity which overcomes the above described problems in prior art.
- The invention provides a solid pharmaceutical formulation comprising amorphous dapagliflozin. The solid pharmaceutical formulation does not comprise described problems in prior art about active agent. The formulation provides long shelf life and high stability during shelf life. Also, the solid pharmaceutical formulation comprising amorphous dapagliflozin provides the desired bioavailability.
- According to an embodiment of the present invention, a solid pharmaceutical formulation comprising amorphous dapagliflozin and at least one pharmaceutically acceptable excipient.
- As used here in, 'particle size' means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis). The term d (0.1) means, the size at which 10% by volume of the particles are finer and d (0.5) means the size at which 50% by volume of the particles are finer and d (0.9) means the size at which %90 by volume of the particles are finer.
- We have found that dapagliflozin having the following particle sizes is very important for formulation. Especially, it positively affects the dissolution properties and powder homogenization. The obtained tablets have the desired dissolution profile. The powder is more homogeneous. The content uniformity of the tablets obtained from the more homogeneous powder is more ideal. Therefore, it provides better bioavailability.
- According to an embodiment of the present invention, amorphous dapagliflozine has a d (0.9) particle size between 20 µm to 140 µm.
- According to an embodiment of the present invention, amorphous dapagliflozine has a d (0.9) particle size between 22 µm to 130 µm, between 25 µm to 120 µm, between 30 µm to 110 µm, between 35 µm to 100 µm, between 40 µm to 98 µm, between 45 µm to 95 µm, between 47 µm to 90 µm, between 50 µm to 85 µm.
- According to an embodiment of the present invention, amorphous dapagliflozine has a d (0.1) particle size between 3 µm to 60 µm.
- According to an embodiment of the present invention, amorphous dapagliflozine has a d (0.1) particle size between 5 µm to 55 µm, between 6 µm to 50 µm, between 7 µm to 45 µm, between 8 µm to 40 µm, between 9 µm to 30 µm.
- According to an embodiment of the present invention, amorphous dapagliflozine has a d (0.5) particle size between 8 µm to 90 µm.
- According to an embodiment of the present invention, amorphous dapagliflozine has a d (0.5) particle size between 9 µm to 85 µm, between 10 µm to 80 µm, between 11 µm to 75 µm, between 11 µm to 70 µm, between 15 µm to 60 µm, between 18 µm to 55 µm, between 20 µm to 50 µm, between 25 µm to 45 µm.
- According to an embodiment of the present invention, the amount of amorphous dapagliflozin is 0.05% to 8.0% by weight, preferably 0.05.% to 5.0% by weight in the total composition.
- Dapagliflozin is used small proportion that can lead to considerable problems during the manufacture of the composition with regard to the uniformity of the content of active agent in the individual composition units. Because of problems uniformity of the content, the active substance may interact with several excipients. It reflects that content uniformity play important role in the dissolution of the drug. Using the right excipients is ensured uniformity of the content.
- According to an embodiment of the present invention, at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
- Suitable fillers are selected from the group comprising microcrystalline cellulose, anhydrous lactose, lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, silicon dioxide, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.
- According to an embodiment of the present invention, the filler is microcrystalline cellulose or anhydrous lactose.
- According to an embodiment of the present invention, the amount of fillers is 5.0% to 92% by weight.
- According to an embodiment of the present invention, the amount of fillers is 5.0% to 40.0% or 58.0% to 92.0% by weight in the total composition.
- Suitable binders are selected from the group comprising polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, carboxymethylcellulose sodium, lactose anhydrous, pregelatinized starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulphate, hydroxypropylcellulose, methyl cellulose, ethyl cellulose or mixtures thereof.
- According to an embodiment of the present invention, the binder is polyvinylpyrrolidone or hydroxypropylmethylcellulose or carboxymethylcellulose sodium.
- According to an embodiment of the present invention, the amount of binders is 0.5% to 15% by weight in the total composition. This amount of binders provides the desired dissolution profile.
- Suitable disintegrants are selected from the group comprising croscarmellose sodium, crospovidone, sodium starch glycollate, sodium alginate, gums, starch and magnesium aluminum silicate or a mixture thereof.
- According to an embodiment of the present invention, the disintegrant is croscarmellose sodium or crospovidone.
- According to an embodiment of the present invention, the amount of disintegrants is 0.05% to 10.0% by weight, preferably 1.0% to 4.0% by weight in the total composition. This amount of disintegrants provides the desired dissolution profile.
- Suitable glidant are selected from group comprising colloidal silicon dioxide, magnesium oxide, starch, magnesium silicate, colloidal silica or mixtures thereof.
- According to an embodiment of the present invention, the glidant is colloidal silicon dioxide.
- According to an embodiment of the present invention, the amount of glidants is 0.05% to 3.0% by weight in the total composition.
- Suitable lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, silica colloidal anhydrous, talc, polyethylene glycol, stearic acid, aluminum silicate or mixtures thereof.
- According to an embodiment of the present invention, the lubricant is magnesium stearate or sodium stearyl fumarate.
- According to an embodiment of the present invention, the amount of lubricants is 0.01% to 5.0% by weight in the total composition.
- According to an embodiment of the present invention, in the solid pharmaceutical formulation, modified release formulations can be preferred. Modified release formulations are selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof. At this invention, formulation is prepared using matrix agents.
- Suitable matrix agents are selected from the group comprising hydroxypropylmethyl cellulose, ethyl cellulose, polymethylmethacrylate derivatives's, poloxamer, polyvinyl alcohol, xanthan gum, sodium alginate, polymethacrylates, polyacrylamide, semi-synthetic polymers such as methyl cellulose, hydroxypropyl cellulose, polyvinyl acetate, cellulose acetate phthalate, ethylene vinyl acetate, methyl aminoethyl methacrylate, neutral methacrylic acid esters, polylactide, polylactide co-glycolide, low molecular weight polyethylene/polyisobutylene, polyanhydrides and poly (ortho-esters), diethyl aminoethyl methacrylate or mixtures thereof. The amount of matrix agents is 10.0% to 30.0% by weight in the total composition.
- According to an embodiment of the present invention, the solid pharmaceutical formulation is in the form of film-coated tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, pellet, buccal tablet, sublingual tablet, effervescent tablet, capsule.
- According to an embodiment of the present invention, the solid pharmaceutical formulation is in the form of film-coated tablet which comprises at least one film coating agent.
- Suitable film coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, talc, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, glycerin, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), iron oxide yellow, iron oxide, all kinds of Opadry®, pigments, dyes, titanium dioxide, coloring agent or mixtures thereof.
- According to an embodiment of the present invention, the film coating agents are selected from the group comprising polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, iron oxide, iron oxide yellow.
- According to an embodiment of the present invention, the amount of film coating agents is 1.0% to 10.0% by weight, preferably 1.5 to 6.0% by weight in the total composition.
- According to an embodiment of the present invention, the solid pharmaceutical formulation is in the form of bilayer tablet or multilayer tablet.
- According to an embodiment of the present invention, amorphous dapagliflozin is present in a combination therapy. Especially; combinations can be with at least one dipeptidyl peptidase-4 (DPP-4) inhibitor agent. For example; amorphous dapagliflozin and metformin hydrochloride, amorphous dapagliflozin and saxagliptin in the form the free base or in the form of pharmaceutically acceptable salts, amorphous dapagliflozin and saxagliptin in the form the free base or in the form of pharmaceutically acceptable salts and metformin HCI, amorphous dapagliflozin and sitagliptin in the form the free base or in the form of pharmaceutically acceptable salts.
- According to an embodiment of the present invention, amorphous dapagliflozin is present in a combination therapy which are with metformin HCl or saxagliptin in the form the free base or in the form of pharmaceutically acceptable salts or sitagliptin in the form the free base or in the form of pharmaceutically acceptable salts or mixtures thereof.
- The solid pharmaceutical formulation of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet granulation or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
-
Active ingredient and excipient Ingredients in one tablet (%) (by weight) Amorphous dapagliflozin 0.05 - 8.0 Microcrystalline cellulose 50.0 - 80.0 Anhydrous lactose 8.0 - 25.0 Crospovidone 1.0 - 10.0 Colloidal silicone dioxide 0.5 - 5.0 Magnesium stearate 0.5 - 5.0 Film coating agents 1.0 - 8.0 Total 100 -
Active ingredient and excipient Ingredients in one tablet (%) (by weight) Amorphous dapagliflozin 3.8 Microcrystalline cellulose 66.8 Anhydrous lactose 19.2 Crospovidone 3.8 Colloidal silicone dioxide 1.5 Magnesium stearate 1.0 Film coating agents 3.8 Total 100 -
- a) Mixing amorphous dapagliflozin, microcrystalline cellulose, anhydrous lactose, crospovidone and colloidal silicone dioxide,
- b) Adding magnesium stearate and then mixing,
- c) Compressing the mixture to form of tablet,
- d) Coating tablets with film coating agents.
-
Active ingredient and excipient Ingredients in one tablet (%) (by weight) Amorphous dapagliflozin 0.05 - 5.0 Metformin HCl 55.0 - 80.0 Polyvinylpyrrolidone 2.0 - 15.0 Microcrystalline cellulose 5.0 - 30.0 Croscarmellose sodium 1.0 - 10.0 Magnesium stearate 0.1 -5.0 Film coating agents 2.0 - 10.0 Total 100 -
Active ingredient and excipient Ingredients in one tablet (%) (by weight) Amorphous dapagliflozin 0.3 Metformin HCI 68.5 Polyvinylpyrrolidone 5.5 Microcrystalline cellulose 16.8 Croscarmellose sodium 2.4 Magnesium stearate 1.0 Film coating agents 5.5 Total 100 -
- a) Mixing amorphous dapagliflozin, metformin HC, croscarmellose sodium, microcrystalline cellulose,
- b) Dissolving polyvinylpyrrolidone in pure water to obtained a solution,
- c) Spraying the solution with the mixture at step (a).
- d) Drying the mixture, then sieving the mixture,
- e) Adding magnesium stearate and then mixing,
- f) Compressing the mixture to form of tablet,
- g) Coating tablets with film coating agents.
-
Active ingredient and excipient Ingredients in one layer (%) (by weight) The immediate release layer (first layer) Amorphous dapagliflozin 0.1 -8.0 Microcrystalline cellulose 5.0 - 30.0 Anhydrous lactose 1.0 - 10.0 Croscarmellose sodium 0.05 - 3.0 Colloidal silicon dioxide 0.05 - 3.0 Sodium stearyl fumarate 0.05 - 3.0 The extended release layer (second layer) Metformin HCI 40.0 - 80.0 At least one matrix agent (for example; hydroxypropyl methylcellulose (HPMC K100 MCR/K100/CN10T)) 10.0 - 30.0 Hydroxypropylmethyl cellulose as binder 0.1 - 6.0 Carboxymethylcellulose sodium 0.5 - 6.0 Magnesium stearate 0.01 - 3.0 Film-coating Film coating agents 1.0 - 8.0 Total of the weight of the bilayer tablet 100 -
Active ingredient and excipient Ingredients in one layer (%) (by weight) The immediate release layer (first layer) Amorphous dapagliflozin 0.6 Microcrystalline cellulose 11.7 Anhydrous lactose 2.9 Croscarmellose sodium 0.9 Colloidal silicon dioxide 0.3 Sodium stearyl fumarate 0.4 The extended release layer (second layer) Metformin HCI 59.9 At least one matrix agent 16.4 Hydroxypropylmethylcellulose as binder 1.2 Carboxymethylcellulose Sodium 3.0 Magnesium stearate 0.4 Film-coating Film coating agents 2.4 Total of the weight of the bilayer tablet 100 -
- 1. The immediate release layer
- a. Mixing amorphous dapagliflozin and colloidal silicon dioxide,
- b. Adding anhydrous lactose and croscarmellose sodium,
- c. Adding microcrystalline cellulose and then mixing,
- d. Adding sodium stearyl fumarate and then mixing,
- 2. The extended release layer
- a. Mixing metformin HCI, carboxymethylcellulose sodium, hydroxypropyl methylcellulose
- b. Spraying the mixture with pure water,
- c. Drying the mixture, then sieving the mixture,
- d. Adding hydroxypropylmethylcellulose (HPMC K100 MCR/K100/CN10T) and then mixing,
- e. Adding magnesium stearate and then mixing,
- 3. Compressing the immediate release layer and extended release layer to form of a bilayer tablet,
- 4. Coating bilayer tablets with film coating agents.
Claims (15)
- A solid pharmaceutical formulation comprising amorphous dapagliflozin and at least one pharmaceutically acceptable excipient.
- The solid pharmaceutical formulation according to claim 1, wherein amorphous dapagliflozine has a d (0.9) particle size between 20 µm to 140 µm.
- The solid pharmaceutical formulation according to claim 1, wherein amorphous dapagliflozine has a d (0.1) particle size between 3 µm to 60 µm.
- The solid pharmaceutical formulation according to claim 1, wherein amorphous dapagliflozine has a d (0.5) particle size between 8 µm to 90 µm.
- The solid pharmaceutical formulation according to claim 1, wherein the amount of amorphous dapagliflozin is 0.05% to 8.0% by weight, preferably 0.05.% to 5.0% by weight in the total composition.
- The solid pharmaceutical formulation according to claim 1, wherein at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
- The solid pharmaceutical formulation according to claim 6, wherein fillers are selected from the group comprising microcrystalline cellulose, anhydrous lactose, lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, silicon dioxide, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.
- The solid pharmaceutical formulation according to claim 6, wherein binders are selected from the group comprising polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, carboxymethylcellulose sodium, lactose anhydrous, pregelatinized starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulphate, hydroxypropylcellulose, methyl cellulose, ethyl cellulose or mixtures thereof.
- The solid pharmaceutical formulation according to claim 8, wherein the amount of binders is 0.5% to 15% by weight in the total composition.
- The solid pharmaceutical formulation according to claim 6, wherein disintegrants are selected from the group comprising croscarmellose sodium, crospovidone, sodium starch glycollate, sodium alginate, gums, starch and magnesium aluminum silicate or a mixture thereof.
- The solid pharmaceutical formulation according to claim 10, wherein the amount of disintegrants is 0.05% to 10.0% by weight in the total composition.
- The solid pharmaceutical formulation according to claim 6, wherein glidant are selected from group comprising colloidal silicon dioxide, magnesium oxide, starch, magnesium silicate, colloidal silica or mixtures thereof.
- The solid pharmaceutical formulation according to claim 6, wherein lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, silica colloidal anhydrous, talc, polyethylene glycol, stearic acid, aluminum silicate or mixtures thereof.
- The solid pharmaceutical formulation according to claim 1, wherein the formulation is in the form of film-coated tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, pellet, buccal tablet, sublingual tablet, effervescent tablet, immediate release tablet, modified release tablet, capsule.
- The solid pharmaceutical formulation according to claim 1, wherein amorphous dapagliflozin is present in a combination therapy which are with metformin HCI or saxagliptin in the form the free base or in the form of pharmaceutically acceptable salts or sitagliptin in the form the free base or in the form of pharmaceutically acceptable salts or mixtures thereof.
Applications Claiming Priority (1)
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TR2020/19592A TR202019592A2 (en) | 2020-12-03 | 2020-12-03 | Solid pharmaceutical formulations of amorphous dapagliflozin |
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EP4008317A1 true EP4008317A1 (en) | 2022-06-08 |
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EP21211906.9A Pending EP4008317A1 (en) | 2020-12-03 | 2021-12-02 | Solid pharmaceutical formulations of amorphous dapagliflozin |
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EP (1) | EP4008317A1 (en) |
TR (2) | TR202019592A2 (en) |
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- 2021-12-02 EP EP21211906.9A patent/EP4008317A1/en active Pending
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TR202019592A2 (en) | 2022-06-21 |
WO2022119542A1 (en) | 2022-06-09 |
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